Membrane-Mediated Alterations of Intracellular Na+ and K+ in Lytic-Virus-Infected and Retrovirus-Transformed Cells

Infection of chick-embryo fibroblasts and other ceils by certain animal viruses results in alterations in the intracellular concentrations of Na + and K +. Dramatic alterations in monovalent-cation concentrations of lytic-virus-infected ceils may favor the synthesis of viral proteins over cellular proteins. More subtle alterations in retrovirus-transformed cells may result in the expression of many morphological and biochemical changes associated with the transformed phenotype.Public Health Service Grant CA 26169, CA 27003National Cancer Institute CA 06593Integrative Biolog

Editor's Choice - Re-interventions After Repair of Ruptured Abdominal Aortic Aneurysm: A Report From the IMPROVE Randomised Trial.

OBJECTIVE/BACKGROUND: The aim was to describe the re-interventions after endovascular and open repair of rupture, and investigate whether these were associated with aortic morphology. METHODS: In total, 502 patients from the IMPROVE randomised trial (ISRCTN48334791) with repair of rupture were followed-up for re-interventions for at least 3 years. Pre-operative aortic morphology was assessed in a core laboratory. Re-interventions were described by time (0-90 days, 3 months-3 years) as arterial or laparotomy related, respectively, and ranked for severity by surgeons and patients separately. Rare re-interventions to 1 year, were summarised across three ruptured abdominal aortic aneurysm trials (IMPROVE, AJAX, and ECAR) and odds ratios (OR) describing differences were pooled via meta-analysis. RESULTS: Re-interventions were most common in the first 90 days. Overall rates were 186 and 226 per 100 person years for the endovascular strategy and open repair groups, respectively (p = .20) but between 3 months and 3 years (mid-term) the rates had slowed to 9.5 and 6.0 re-interventions per 100 person years, respectively (p = .090) and about one third of these were for a life threatening condition. In this latter, mid-term period, 42 of 313 remaining patients (13%) required at least one re-intervention, most commonly for endoleak or other endograft complication after treatment by endovascular aneurysm repair (EVAR) (21 of 38 re-interventions), whereas distal aneurysms were the commonest reason (four of 23) for re-interventions after treatment by open repair. Arterial re-interventions within 3 years were associated with increasing common iliac artery diameter (OR 1.48, 95% confidence interval [CI] 0.13-0.93; p = .004). Amputation, rare but ranked as the worst re-intervention by patients, was less common in the first year after treatment with EVAR (OR 0.2, 95% CI 0.05-0.88) from meta-analysis of three trials. CONCLUSION: The rate of mid-term re-interventions after rupture is high, more than double that after elective EVAR and open repair, suggesting the need for bespoke surveillance protocols. Amputations are much less common in patients treated by EVAR than in those treated by open repair

Meta-analysis of individual-patient data from EVAR-1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 years

Background: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation.Methods: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention.Results: The analysis included 2783 patients, with 14 245 person-years of follow-up (median 5.5years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0.61, 95 per cent c. i. 0.42 to 089; P = 0010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 040, 95 per cent c. i. 022 to 074). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 516, 149 to 1789; P = 0010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0022) in the period from 6 months to 4 years after randomization.Conclusion: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM(Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anevrysme de l'aorte abdominale, Chirurgie versus Endoprothsse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.</p

Regional brain metabolism in a murine systemic lupus erythematosus model

Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and antinuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb + mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb + mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb + animals with hippocampal BBB breach and altered fear conditioning in DNRAb + mice with amygdala BBB breach. In DNRAb + mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects

Analysis of clinical benefit, harms, and cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme

Endovascular or open repair strategy for ruptured abdominal aortic aneurysm: 30 day outcomes from IMPROVE randomised trial.

OBJECTIVE: To assess whether a strategy of endovascular repair (if aortic morphology is suitable, open repair if not) versus open repair reduces early mortality for patients with suspected ruptured abdominal aortic aneurysm. DESIGN: Randomised controlled trial. SETTING: 30 vascular centres (29 UK, 1 Canadian), 2009-13. PARTICIPANTS: 613 eligible patients (480 men) with a clinical diagnosis of ruptured aneurysm. INTERVENTIONS: 316 patients were randomised to the endovascular strategy (275 confirmed ruptures, 174 anatomically suitable for endovascular repair) and 297 to open repair (261 confirmed ruptures). MAIN OUTCOME MEASURES: 30 day mortality, with 24 hour and in-hospital mortality, costs, and time and place of discharge as secondary outcomes. RESULTS: 30 day mortality was 35.4% (112/316) in the endovascular strategy group and 37.4% (111/297) in the open repair group: odds ratio 0.92 (95% confidence interval 0.66 to 1.28; P=0.62); odds ratio after adjustment for age, sex, and Hardman index 0.94 (0.67 to 1.33). Women may benefit more than men (interaction test P=0.02) from the endovascular strategy: odds ratio 0.44 (0.22 to 0.91) versus 1.18 (0.80 to 1.75). 30 day mortality for patients with confirmed rupture was 36.4% (100/275) in the endovascular strategy group and 40.6% (106/261) in the open repair group (P=0.31). More patients in the endovascular strategy than in the open repair group were discharged directly to home (189/201 (94%) v 141/183 (77%); P<0.001). Average 30 day costs were similar between the randomised groups, with an incremental cost saving for the endovascular strategy versus open repair of £1186 (€1420; $1939) (95% confidence interval -£625 to £2997). CONCLUSIONS: A strategy of endovascular repair was not associated with significant reduction in either 30 day mortality or cost. Longer term cost effectiveness evaluations are needed to assess the full effects of the endovascular strategy in both men and women. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48334791

Current prevalence of screen-detected abdominal aortic aneurysm in women: a systematic review with meta-analysis

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Wiley.Background: Although women represent an increasing proportion of those now presenting with abdominal aortic aneurysm (AAA) rupture, the current prevalence of AAA in women is unknown. The contemporary population prevalence of screen-detected AAA in women by both age and smoking status was investigated. Methods: Systematic review of studies screening for AAA, including >1000 women, aged ≥60 years, undertaken since the year 2000, searching MEDLINE, EMBASE and CENTRAL databases until 13th January 2016. Study quality was assessed using the Newcastle-Ottawa scoring system. Results: Eight studies were identified, including only 3 based on population registers. The largest studies were based on self-purchase of screening. Altogether 1,537,633 women were screened. Overall AAA prevalence rates were very heterogeneous, ranging from 0.37 to 1.53%: pooled prevalence 0.74% [95%CI 0.53, 1.03]. The pooled prevalence increased with both age (>1% for women >70 years) and smoking (>1% for ever smokers and >2% in current smokers). Conclusions: The current population prevalence of screen-detected AAA in older women is subject to wide demographic variation. However, in ever smokers and those over 70 years, the prevalence is >1%. Registration: PROSPERO database of systematic reviews CRD42015020444This project was funded by the UK National Institute for Health Research (NIHR) Health Technology Appraisal (HTA) programme (project number 14/179/01)